Microtubule organization and sensory neuron dysfunction in neuropathic pain states in mice and humans

• Antragsteller: Dr. Paul A. Heppenstall
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2013 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 235105306

Neuropathic pain is a major and debilitating condition that arises from lesion of the nervous system. Therapeutic strategies for treating neuropathic pain are often ineffective and underlying mechanisms are poorly understood. In this proposal we will investigate a relatively unexplored factor in the pathogenesis of neuropathic pain, the role of sensory neuron microtubules. Using a combination of animal model and human studies we will determine whether microtubule organization is disrupted in neuropathy and whether posttranslation modification of tubulin is a contributing factor to this process. In the first part of the project we will explore the functional significance of a prominent microtubule posttranslation modification in neurons, tubulin acetylation. We will focus on a recently identified microtubule modifying enzyme, aTAT1, which is believed to be the major a-tubulin acetyltransferase in ciliated organisms. Using conditional mouse transgenesis we will examine the function of aTAT1 in peripheral sensory neurons and determine whether ablation of the Atat1 gene disrupts microtubule organization and leads to sensory neuron dysfunction. In the second part of the project we will investigate microtubule function in neuropathic pain states. Using clinically relevant mouse models of chemotherapy and mechanically induced neuropathy we will measure nociceptive behavior in aTAT1 mutant mice and assess key features of sensory neuron microtubule organization following nerve injury. We aim to establish whether microtubules are important molecular mediators of painful neuropathy and whether acetylation is a critical regulatory mechanism for this process. The third part of the project will focus on delineating the function of microtubules in human neuropathic pain patients. We will evaluate microtubule organization at the ultrastructural, cellular and tissue level in skin samples from neuropathic pain patients. By comparing key properties of microtubule structure, organization and function in skin from patients with painful and non-painful neuropathy, and from painful and non-painful body areas, we aim to determine whether microtubules play a causative role in neuropathic pain. This project is designed to utilize the potential of conditional mouse genetics coupled with the clinical relevance of human studies. We hope that this approach will allow us to discover novel molecular pathways involved in neuropathic pain in humans and ultimately to define new therapeutic strategies for treating this condition.

• DFG-Verfahren: Sachbeihilfen